This research program is designed to provide information on the mode(s) of phototoxicity associated with the use of photodynamic therapy for cancer control. The long-range goal is the design of sensitizer protocols with improved efficacy. We will focus on the role of tumor vs. tumor vasculature as targets for PDT using cationic photosensitizers and the transplantable FANFT-induced urothelial rat tumor. In vitro and in vivo. This tumor expresses the mdr gene product, the multidrug transporter. This outward transport system. mediated by P-glycoprotein, recognizes as substrates cationic agents of appropriate hydrophobicity. Neoplastic cells which express MDR are thereby protected from photodamage by substrates recognized by the transporter. but photodamage to the tumor vasculature is not prevented since vascular MDR expression is confined to the CNS. We have identified two cationic photosensitizers which are substrates for the multidrug transporter and one which is not. These agents are members of a series of benzochlorin iminium salts developed by Dr. Alan Morgan, who will provide the sensitizers and carry out selected in vivo studies on PDT efficacy. The latter will involve sequential irradiation protocols which can selectively activate each benzochlorin. Dr. Victor Fingar will be responsible for experiments designed to assess direct cytotoxicity vs. vascular damage as factors in tumor response in these solid tumors. Studies to be carried out at Wayne State University, will provide information on sensitizer pharmacokinetics modes of tumor phototoxicity and sensitizer localization, which can then be compared with vascular and non-vascular PDT responses. Studies on effects of photodamage to the P- glycoprotein may also provide information on sites of binding of substrates to this transport protein. The role of apoptotic vs. necrotic cell death resulting from direct tumor cell kill vs. vascular shut-down will also be examined.